Treatment-resistant and aggressive tumors that cannot be fully and safely resected with surgery, and recur despite chemo- and radio-therapies, cause the lowest survival rate and quality of life among cancer patients. This over-arching oncology problem will be addressed with novel physical approaches to create self-regulated cell level cancer treatment. This will be realized through on-demand physical intracellular non-stationary events whose efficacy is self-amplified in cells with cancer aggressiveness, and whose safety is ensured by their stealth and cancer cell-specific nature. Such event is plasmonic nanobubble (PNB) - an intracellular explosion triggered with a short laser pulse around an intracellular cluster of plasmonic (gold) colloids that remain safe and passive until activated. Intracellular PNB creates the mechanical non-stationary threshold-activated effects that detect and destroy cancer cells and efficiently convert surgery, chemo- and radio-therapies into the cell level modality through a simple protocol by using low doses of only clinically-approved components. The innovative nature of this physical approach in cancer is in merging the mechanical event with the biological mechanisms to transform current macro-medicine into a cancer cell-specific on-demand intracellular treatment. The intracellular synergy of three PNB effects - mechanical intracellular impact, intracellular drug ejection from internalized liposomes and amplification of the external radiation - radically amplifies the therapeutic efficacy as compared to standard material-based treatments, and this therapeutic amplification increases with the gold cluster size which is driven by the cancer aggressiveness. This proposal will explore the hypothesis that that the mechanical impact of PNB will overcome cancer resistance and will convert standard surgery and chemo- and radio- therapies into a cell level on-demand modality whose efficacy will be self-amplified by cancer cell aggressiveness. This approach will be studied in aggressive triple-negative breast cancer (TNBC) as a model. The project will analyze the biological response of cancer cells to non-stationary intracellular mechanical impact in vitro and physiological response of resistant and aggressive tumor to non-stationary mechanical impact in vivo to radically amplify the efficacy of standard treatments without increasing their doses and non- specific toxicity. As a result, the self-regulated intracellular therapeutic PNB-based mechanisms (mechanical drugs) will be developed to treat aggressive and resistant tumors, and will estimate optimal clinical applications of PNB mechanisms within existing standards of care. The project will bring several benefits. In science, the multifunctiona intracellular PNBs will merge the physical and biological approaches in novel therapeutic mechanisms. In oncology, PNBs will support the intracellular amplification of standard clinical modalities when the latter fail, will broaden the patient eligibility by offering a safe, new treatment to those patients who currently are referred only to palliative care and will offer a new efficient use of standard under-recognized drugs currently considered inefficient.